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Beagrie, R.A.* ; Thieme, C.J.* ; Annunziatella, C.* ; Baugher, C.* ; Zhang, Y.* ; Schueler, M.* ; Kukalev, A.* ; Kempfer, R.* ; Chiariello, A.M.* ; Bianco, S.* ; Li, Y.* ; Davis, T.* ; Scialdone, A. ; Welch, L.R.* ; Nicodemi, M.* ; Pombo, A.*

Multiplex-GAM: genome-wide identification of chromatin contacts yields insights overlooked by Hi-C.

Nat. Methods 20, 1037-1047 (2023)

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Technology for measuring 3D genome topology is increasingly important for studying gene regulation, for genome assembly and for mapping of genome rearrangements. Hi-C and other ligation-based methods have become routine but have specific biases. Here, we develop multiplex-GAM, a faster and more affordable version of genome architecture mapping (GAM), a ligation-free technique that maps chromatin contacts genome-wide. We perform a detailed comparison of multiplex-GAM and Hi-C using mouse embryonic stem cells. When examining the strongest contacts detected by either method, we find that only one-third of these are shared. The strongest contacts specifically found in GAM often involve ‘active’ regions, including many transcribed genes and super-enhancers, whereas in Hi-C they more often contain ‘inactive’ regions. Our work shows that active genomic regions are involved in extensive complex contacts that are currently underestimated in ligation-based approaches, and highlights the need for orthogonal advances in genome-wide contact mapping technologies.

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